Methods, systems, and devices for treating tinnitus with VNS pairing

ABSTRACT

A method of treating tinnitus comprising measuring a patient&#39;s hearing, determining the patient&#39;s hearing loss and the patient&#39;s tinnitus frequency using the measurements of the patient&#39;s hearing, programming a clinical controller with the measurements of the patient&#39;s hearing, selecting a plurality of therapeutic tones, where the therapeutic tones are selected to be at least a half-octave above or below of the patient&#39;s tinnitus frequency, setting an appropriate volume for each of the plurality of tones, repetitively playing each of the plurality of therapeutic tones, and pairing a vagus nerve stimulation pulse train with each playing of a therapeutic tone, thereby reducing the patient&#39;s perception of tinnitus.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/699,470, filed Sep. 11, 2012, U.S. Provisional PatentApplication No. 61/614,369, filed Mar. 22, 2012, U.S. Provisional PatentApplication No. 61/598,185, filed Feb. 13, 2012, and U.S. ProvisionalPatent Application No. 61/558,287, filed Nov. 10, 2011. This applicationis also a Continuation-In-Part of U.S. patent application Ser. No.13/095,570, filed Apr. 27, 2011, which claims the benefit of U.S.Provisional Patent Application No. 61/328,621, filed Apr. 27, 2010 andwhich is a Continuation-In-Part of U.S. patent application Ser. No.12/485,040, filed Jun. 15, 2009, which claims the benefit of: U.S.Provisional Patent Application No. 61/077,648, filed Jul. 2, 2008; U.S.Provisional Patent Application No. 61/078,954, filed Jul. 8, 2008; U.S.Provisional Patent Application No. 61/086,116, filed Aug. 4, 2008; andU.S. Provisional Patent Application No. 61/149,387, filed Feb. 3, 2009.All of these applications are incorporated herein by reference as ifreproduced in their entirety.

RELATED APPLICATIONS

The present application is a continuation of application No.13/934,893,filed Jul. 3, 2013, entitled METHODS, SYSTEMS, AND DEVICES FOR TREATINGTINNITUS WITH VNS PAIRING, the disclosure of which is herebyincorporated by reference herein in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

REFERENCE TO A MICROFICHE APPENDIX

Not applicable.

BACKGROUND

Tinnitus is characterized by an auditory sensation in the absence ofexternal sound. Approximately 12 million individuals in the UnitedStates have some degree of tinnitus. About 5 million of these sufferershave severe tinnitus that interferes with their daily activities andtheir quality of life. In fact, severe tinnitus can lead to depressionand other mental health challenges that severely affect the patient andthe patient's family members. Therapies such as masking, sound therapy,electrical stimulation, and drugs have shown some benefit.Unfortunately, these treatments are non-specific and are insufficient toreverse the brain changes that cause tinnitus. Therefore, treatment oftinnitus remains a significant unmet need.

Numerous therapies have been used to treat or alleviate the symptoms oftinnitus. For example, pharmaceutical therapies such as antidepressants,anti-anxiety medications, as well as other medicinal compounds have beenattempted. Neurostimulation techniques including transcranial magneticstimulation and cortical stimulation have been used to alleviatesymptoms. Sound has been used in several ways, including masking therapyauditory exposure and frequency discrimination training.

U.S. Patent Application Publication 2007/0027504 (Barrett) describes asystem for treating tinnitus using vagus nerve stimulation. A patient'svagus nerve was stimulated as the patient experienced tinnitus symptomsto temporarily alleviate the symptoms. No audible tones are specificallypresented or paired in Barrett's therapy.

U.S. Pat. No. 6,990,377 (Gliner) describes a therapy to treat visualimpairments. The therapy includes presenting various types of visualstimuli in conjunction with stimulation of the visual cortex. Thetherapy described in Gliner does not control the timing relationship ofthe stimuli and the stimulation.

U.S. Patent Application Publication 2007/1079534 (Firlik) describes atherapy having patient interactive cortical stimulation and/or drugtherapy. The therapy has patients performing tasks, detecting patientcharacteristics, and modifying the stimulation depending on the detectedpatient characteristics. The therapy described in Firlik does notcontrol the timing relationship between the tasks and the corticalstimulation.

It is common in the prior art to suggest that stimulation of the cortex,the deep brain, the cranial nerves, and the peripheral nerves aresomehow equivalent or interchangeable to produce therapeutic effects.Despite these blanket statements, stimulation at different parts of thenervous system is not equivalent. It is generally understood that thevagus nerve is a nerve that performs unique functions through therelease of a wide array of neuromodulators throughout the brain. Togenerate certain kinds of plasticity, the timing of the stimulation ofthe vagus nerve is critical in producing specific therapeutic effects.

U.S. Pat. No. 6,104,956 (Naritoku) is representative of work done usingvagus nerve stimulation (VNS) to treat a variety of disorders, includingepilepsy, traumatic brain injury, and memory impairment. The VNS isdelivered without any other therapy. To improve memory consolidation,VNS is delivered several minutes after a learning experience. Memoryconsolidation is unrelated to the present therapy for treating tinnitus.

SUMMARY

For purposes of summarizing the disclosure, certain aspects, advantages,and novel features of the disclosure have been described herein. It isto be understood that not necessarily all such advantages may beachieved in accordance with any particular embodiment of the disclosure.Thus, the disclosure may be embodied or carried out in a manner thatachieves or optimizes one advantage or group of advantages as taughtherein without necessarily achieving other advantages as may be taughtor suggested herein.

In an embodiment the disclosure includes a method of treating tinnituscomprising measuring a patient's hearing, determining the patient'shearing loss and the patient's tinnitus frequency using the measurementsof the patient's hearing, programming a clinical controller with themeasurements of the patient's hearing, selecting a plurality oftherapeutic tones, where the therapeutic tones are selected to be atleast a half-octave above or below of the patient's tinnitus frequency,setting an appropriate volume for each of the plurality of tones,repetitively playing each of the plurality of therapeutic tones, andpairing a vagus nerve stimulation pulse train with each playing of atherapeutic tone, thereby reducing the patient's perception of tinnitus.

In another embodiment the disclosure includes a system for treatingtinnitus comprising a clinical controller executing tinnitus therapysoftware, a VNS implantable pulse generator (IPG) in communication withthe clinical controller and receiving stimulation signals from theclinical controller, a VNS lead connected to the VNS IPG, a VNSelectrode connected to the VNS lead and receiving stimulation signalsthrough the VNS lead from the VNS IPG, and headphones connected to theclinical controller, wherein the clinical controller plays selectedsound files through the headphones while sending stimulation signals tothe VNS IPG such that the sound files may be heard by a patient while astimulation pulse train at the VNS electrode causes the patient's vagusnerve to be stimulated.

In yet another embodiment the disclosure includes a method of treatingtinnitus comprising measuring a patient's hearing, determining thepatient's hearing loss and the patient's tinnitus frequency using themeasurements of the patient's hearing, programming a clinical controllerwith the measurements of the patient's hearing, selecting a plurality oftherapeutic tones where the therapeutic tones are selected to be atleast a half-octave above or below of the patient's tinnitus frequency,generating sound files by shaping the selected therapeutic tones using aramp function, modulating the sound files with phase information thatsimulates a sound source location, setting an appropriate volume foreach of the plurality of tones, repetitively playing each of theplurality of therapeutic tones, and pairing a vagus nerve stimulationpulse train with each playing of a therapeutic tone, thereby reducingthe patient's perception of tinnitus.

These and other features will be more clearly understood from thefollowing detailed description taken in conjunction with theaccompanying drawings and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of this disclosure, reference is nowmade to the following brief description, taken in connection with theaccompanying drawings and detailed description, wherein like referencenumerals represent like parts.

FIGS. 1A, 1B, and 1C are graphs depicting aspects of a patient'shearing;

FIG. 2 depicts a pure tone;

FIG. 3A depicts an up ramp tone;

FIG. 3B depicts a down ramp tone;

FIG. 4 depicts location encoded sounds;

FIGS. 5A, 5B, and 5C are graphs of stimulation timing relationships;

FIG. 6 depicts an implantable vagus nerve stimulation system;

FIG. 7 depicts a paired VNS tinnitus therapy system;

FIG. 8 is a flowchart depicting a patient therapy initiation routine;

FIG. 9 is a flowchart depicting a tone selection routine;

FIG. 10 is a flowchart depicting a patient therapy routine;

FIG. 11 is a flowchart depicting a patient home therapy routine;

FIG. 12 is a flowchart depicting a sound file generation routine;

FIG. 13 is a screen shot of the paired VNS tinnitus therapy softwaremenu;

FIG. 14 is a screen shot of an audiogram input screen;

FIG. 15 is a screen shot of an audiogram input screen with sample datainput;

FIG. 16 is a screen shot of interpolated audiogram data;

FIG. 17 is a screen shot of therapeutic tone selection;

FIG. 18 is a screen shot of therapeutic tone selection with a tinnitusfrequency notch;

FIG. 19 is a screen shot of therapeutic tone selection with multipletinnitus frequency notches;

FIG. 20 is a screen shot of therapeutic tone selection with two tinnitusfrequency notches;

FIG. 21 is a screen shot of therapeutic tone volume setting;

FIG. 22 is a screen shot of therapeutic tone selection with additionalnotches;

FIG. 23 is a screen shot of stimulation parameter setting; and

FIG. 24 is a screen shot of therapy delivery.

DETAILED DESCRIPTION

It should be understood at the outset that although an illustrativeimplementation of one or more embodiments are provided below, thedisclosed systems and/or methods may be implemented using any number oftechniques, whether currently known or in existence. The disclosureshould in no way be limited to the illustrative implementations,drawings, and techniques illustrated below, including the exemplarydesigns and implementations illustrated and described herein, but may bemodified within the scope of the appended claims along with their fullscope of equivalents. The present application describes severalembodiments, and none of the statements below should be taken aslimiting the claims generally.

Where block diagrams have been used to illustrate the embodiments, itshould be recognized that the physical location where describedfunctions are performed are not necessarily represented by the blocks.Part of a function may be performed in one location while another partof the same function is performed at a distinct location. Multiplefunctions may be performed at the same location. In a functional blockdiagram, a single line may represent a connection, in general, or acommunicable connection, particularly in the presence of a double line,which may represent a power connection. In either case, a connection maybe tangible, as in a wire, or radiated, as in near-field communication.An arrow may typically represent the direction of communication or poweralthough should not be taken as limiting the direction of connectedflow.

Repeatedly pairing a range of non-tinnitus frequency sounds with VNSreduces the perception of tinnitus sounds in a patient with tinnitus. Noone ever before recognized that playing repeated VNS paired sounds couldreduce symptoms of tinnitus.

A common cause of hearing loss that leads to tinnitus is cochlear damagefrom noise trauma. Elevated synchronous spontaneous activity in thecentral auditory system may account for the tinnitus percept that arisesfollowing hearing loss. As a result, some neurons in the auditory cortexno longer receive their normal input. These neurons start responding toadjacent frequencies, and therefore a population of neurons startsfiring spontaneously and synchronously. This pathological activity isthought to give rise to the tinnitus sensation. Based on theseconsiderations, we developed an approach to reduce the tinnitus perceptby redistributing the frequencies along the auditory tonotopic axis,thus reducing the responsiveness of neurons that had too much input. Ourapproach pairs selected tone presentations other than the tinnitusfrequency with simultaneous stimulation of the vagus nerve to induce aredistribution of the distorted auditory cortical frequency map observedin tinnitus. This approach seems to alleviate the presumed behavioraland neurophysiological correlations of tinnitus in a rat model of thedisease.

The mechanism of our therapy may be referred to as repeated pairedtraining. A repeated paired training is defined as follows:

A “training” may be defined as a discrete event in time that has astarting point and a stopping point. In the case of tinnitus therapy, atraining may be a brief sound, such as a tone with a distinct frequency.

A training may be defined as “paired” when a discrete vagus nervestimulation pulse train, having a starting point and a stopping point,occurs during a training. This requires that the training and VNS startand stop in a manner that links the two together in time. When both thetraining and VNS have stopped, there may follow a period when there isneither training nor VNS. This non-training period allows the brain toperceive the next event as a separate discrete event. The mechanism oftherapy takes advantage of the fact that the brain can distinguishbetween two discrete events close together in time.

A “repeated paired training” may be defined as a recurring sequence ofpaired trainings. The mechanism of our therapy is the cumulative effectof repeated paired trainings.

The vagus nerve is composed of somatic and visceral afferents (e.g.,inward conducting nerve fibers which convey impulses toward a nervecenter such as the brain or spinal cord) and efferents (e.g., outwardconducting nerve fibers which convey impulses to an effector tostimulate it and produce activity). 80% of the fibers in the vagus nerveare afferent fibers; the rest are efferent. The vast majority of vagalnerve fibers are C fibers, with the majority being visceral afferentshaving cell bodies lying in masses or ganglia in the skull. The centralprojections terminate largely in the nucleus of the solitary tract whichsends fibers to various regions of the brain (e.g., the hypothalamus,thalamus, locus ceruleus, and amygdala); others continue to the medialreticular formation of the medulla, the cerebellum, the nucleuscuneatus, and other regions. Afferents activate both ascending anddescending pathways.

The vagus nerve may be contacted at any point along its length or one ofits branches. For instance, stimulating or sensing electrodes may belocated directly on, or close to, the left and/or right vagus nerve(s)in a cervical location. Alternatively, the vagus nerve could bestimulated at a near-diaphragmatic location (e.g., supra-diaphragmaticor sub-diaphragmatic).

Stimulation of the vagus nerve may beneficially activate one or more ofthe gustatory pathways, olfactory pathways, pro-inflammatory oranti-inflammatory pathways, respiratory pathways, cardiac pathways,baroreceptor pathways, and the somatosensory pathways, causing aresponse of neural activity in various areas of the brain. Vagus nervestimulation may also affect neurotransmitter pathways such asnoradrenergic, serotoninergic, dopaminergic catecholaminergic,GABAergic, opioidergic and cholinergic pathways similarly. Neuralactivating circuits may include the circuit of Papez, the mesolimbicpathway, the mesocortical pathway or the nigrostriatal pathway. Theeffect of such responsive effect on the brain tissue may be excitatoryor inhibitory and may potentiate acute and/or long-term changes inneuronal activity.

The afferent vagus nerve feeds in the Nucleus Tractus Solitarius whichin turn feeds into several deep brain nuclei including nucleus basalisand locus ceruleus. Each activation of the vagus nerve results in arelease of acetylcholine from the nucleus basalis and norepinephrinefrom the amygdala and locus ceruleus. These neurotransmitters influencethe cortex and other parts of the brain. The context of this release ofneuromodulators defines the effects.

The release of the neuromodulators resulting from activation of thevagus nerve during a paired sensory event generates plasticity in thecortex that is specific to the sensory event. The pairing effectivelytells the brain what to learn. Activation of the vagus nerve during asensory event such as a sound or sound sequence generates plasticity inthe auditory cortex that is specific to the sound or sound sequencebecause the perception of the sound coincides with the release ofneuromodulators in the auditory cortex. Activation of the vagus nerveduring a motion generates specific plasticity in the motor cortex, againbecause the action and released neuromodulators coincide in the motorcortex. The conjunction of these simultaneous activations generatesspecific plasticity with a very brief window, less than eight secondsfor tinnitus.

Until our experiments, the synergy of these activations wasunappreciated. Presenting a sensory event at the same time as activationof the vagus nerve has an effect on the area of the cortex related tothe sensory event. Timing a sensory event with vagus nerve stimulationactivates the appropriate parts of the brain. The described tinnitustherapy has been developed using these principles and tested clinically.

The tinnitus therapy includes a controlled-timing vagus nervestimulation. The vagus nerve may be stimulated using effective methods,such as direct electrical stimulation. Direct electrical stimulation ofthe vagus nerve may be performed using an implantable vagus nervestimulator or a percutaneous vagus nerve stimulator to provideelectrical pulses to an electrode close to the vagus nerve tissue. Othermethods of stimulating the vagus nerve could be used as appropriate, aslong as the timing of the vagus nerve stimulation can be controlled. Inaccordance with an embodiment of the therapy, an implantable vagus nervestimulation device may be implanted in the patient. Alternatively, apercutaneous lead could be attached to an electrode at the vagus nervethrough the patient's skin to provide stimulation of the vagus nerve.The necessary surgery may be performed in advance of the actual therapy,so the tissue has time to heal.

When the therapy is ready to begin, the patient's hearing and tinnitussymptoms are assessed. An audiogram may be generated by an audiologistto characterize the patient's hearing loss. Tinnitus pitch matching maybe done to measure one or more frequencies at which the patient isexperiencing tinnitus. One patient's hearing is depicted in FIG. 1A, andthe patient's tinnitus symptoms is depicted in FIG. 1B. A range oftherapeutic tones for the patient is depicted in FIG. 1C. Because thehearing and symptoms of every patient is individual and unique, thehearing loss, tinnitus symptoms, and range of therapeutic tones maydiffer from those shown.

Using the knowledge of the patient's hearing loss and the frequency orfrequencies that characterize a patient's tinnitus symptoms, theclinician selects a set of therapeutic tones at frequencies the patientcan hear, not including the patient's tinnitus frequencies. Theclinician may select tones at frequencies ranging from 170 hertz (Hz) to16 kilohertz (kHz) and adjust the intensity accordingly. In accordancewith an embodiment, 25 therapeutic frequencies may be selected. Thedistribution of frequencies may be based on Mel scales.

In accordance with an embodiment, therapeutic tones may be generatedusing pure sine wave tones with a sampling rate of 44,100 Hz. Thisrelatively high sampling rate ensures the tones are pure. The samplingrate should be at least twice as high as the highest frequency beingused as a tone.

Using the data generated by the audiogram, a set of sound files may begenerated for the therapy. A therapeutic tone may be a pure tone, asshown in FIG. 2. A pure tone may be defined as a presentation of asingle frequency that exhibits no harmonic distortions. For the purposeof this therapy, a tone may be said to be pure when the ratio of thesingle frequency to any other frequency (harmonics, ambient noise, etc.)is 20:1 or greater. A tone may be sufficiently pure when only the singlefrequency can be discerned by a patient.

Because a pure tone as a sine wave has an abrupt start and stop, thepresentation of a pure tone can seem to include unpleasant pops at thebeginning and end of the tone. To prevent this phenomenon, a 4-10millisecond ramp can be introduced to modulate the start and stop. Aramp up, as shown in FIG. 3A, may be used at the start of the tone and aramp down, as shown in FIG. 3B, may be used before the stop.

The brain may struggle when presented with a stereo in-phase, equalamplitude pure tone, because the lack of location information in thissimple tone makes it impossible for the mind to place the source of thesound in space. To make the tone presentation more natural, to give thesound an apparent location in space both in terms of direction anddistance, the therapy may include phase and amplitude adjustmentsbetween the left and right headphone speakers, so that a tone is heardby the patient as existing at a specific location in space.

Encoding multiple locations which are applied randomly to the tones maybe important, because training an association between a specific toneand a specific location may have adverse consequences. We do not want totrain the patient to pay attention to only one location or tone, butrather have the VNS occur at random locations and frequencies.

A variety of models can be used to encode locations and environments. Inaccordance with one embodiment, a rectangular room, with a drop ceiling,carpet, four walls, and microphones at specific locations provides themodel environment. The model environment simulates the echoes, delays,and absorption at the microphone. Output is determined at seventeenlocations in each of the two rooms. A second environment may be onewhere all walls completely absorb sound, which is effectively the sameas being outdoors.

For the 34 locations in the two rooms, a set of impulse functions isgenerated. Each of these impulse functions is multiplied with a sinewave of a selected frequency to create a complex tone waveform for thatlocation, distance, room, and tone, as shown in FIG. 4. To create thesense of a tone coming from a specific location in space, the sound forthe right ear is given an intensity I_(R) and the sound for the left earis given an intensity I_(L) and the left and right sounds are separatedwith a time delay (φ). By changing the intensity values and the timedelay, the sounds will seem to be coming from different locations inspace, in different environments.

The clinician may test the volume setting of the device before thetherapy begins. The volume of the tones should be audible andcomfortable to the patient. Because a pure tone necessarily has a louderoutput than a complex tone waveform, pure tones may be used to check thevolume settings.

In accordance with an embodiment, each of the 36 (34 locations+right andleft pure tones) complex tone waveforms are multiplied with each of the25 selected therapeutic tones to provide 900 left and right sound files.These sound files may be stored on the clinical controller. The clinicalcontroller includes a soundcard connected to stereo headphones. When theclinical controller plays a sound file, the soundcard converts the soundfile to an output that is received by the stereo headphones andconverted to audible sound. Because each soundcard and headphone has aunique frequency response, they may introduce variables that may need tobe compensated. Typically, the therapy is conducted at 80 decibels (dB)or less. Headphones and soundcards may introduce harmonics anddistortions volumes higher than 80 dB. A patient may need to be able tohear a reasonable number (at least two) of tones at 80 dB.

The tinnitus therapy may be summarized as follows: The patient has animplantable VNS device implanted so that it can provide stimulation tothe patient's vagus nerve on command. An audiologist generates anaudiogram for the patient. The tinnitus frequency or frequencies aredetermined. The frequency of each therapeutic sound or tone is selectedby the audiologist or clinician based on the tinnitus frequency. Theapparent location of each tone is established by the audiologist,clinician, or an automated process that provides a suitable selection ofperceived tone locations. The tone may be shaped by a ramp. Theclinician goes through a software setup procedure, and a clinical setupis performed.

The intensity of each therapeutic tone is set. Typically the intensityis assigned an initial value. A clinician may check with the patient todetermine if the initial intensity settings are appropriate and maychange the intensity of one or more tones accordingly. The intensity maybe calculated from the audiogram data. Feedback loops may beincorporated for automatic control of intensity. From the intensity, thevoltage required to produce the tone is determined. Typically this isperformed by software, automatically.

An audiogram is generated by an audiologist and provided as input to thesoftware. The audiogram measures the hearing loss at each frequency,measured in dB Hearing Loss (HL). The data from the audiogram is thenconverted from a hearing loss measure into dB Sound Pressure Level(SPL). A sound check may be performed. The tinnitus therapy, once set upby the clinician, may be performed by the patient at home. The softwaremay give options to the clinician to set-up the therapy for home use, inparticular to allow the patient to deliver the therapy to themself, athome, while not allowing the patient to change the parameters of thetherapy.

The software is designed to deliver the therapeutic tones and the vagusnerve stimulation to the patient at the same time. In accordance with anembodiment, the therapeutic tones are each about 500 milliseconds induration and the vagus nerve stimulation pulse train is about 500milliseconds. In accordance with an embodiment, a therapy session mayinclude about 300 therapeutic tones paired with about 300 vagus nervestimulations. In accordance with an embodiment, a therapy regime mayinclude about six weeks of therapy sessions, provided about five timesper week. The tinnitus therapy includes a number of variables that maybe changed, as appropriate.

In accordance with an embodiment, the therapeutic tones are about 500milliseconds. The duration of the therapeutic tones may be made longeror shorter. FIG. 5A depicts a relative timing diagram for the tone andvagus nerve stimulation pulse train. FIG. 5B depicts a relative timingdiagram for a plurality of tones and vagus nerve stimulation pulsetrains. FIG. 5C depicts a relative timing diagram for randomly spacedtones and vagus nerve stimulation pulse trains.

In accordance with an embodiment, twenty-five therapeutic tones areselected by the clinician. The twenty-five tones may be selected atregular intervals through frequencies that can be heard by the patient,except the frequencies that characterize the patient's tinnitus orwithin a half-octave of the tinnitus frequencies. More or less tones maybe selected as appropriate. The vagus nerve stimulation pulse trainsdelivered to the patient are 500 milliseconds in duration. The durationof the vagus nerve stimulation pulse trains may be longer or shorter asappropriate. The vagus nerve stimulation pulse trains delivered to thepatient are about 0.8 milliamps. The intensity of the stimulation may bemore or less than 0.8 milliamps, as appropriate. The intensity of thetones being delivered to the patient should be set to a level that iscomfortable for the patient. Depending on a patient's hearing loss, theintensity of the tones may be set to a normal level or a higher level.In accordance with an embodiment, the therapeutic tones and vagus nervestimulations are delivered at the same time, within a few milliseconds.It may be appropriate to begin the therapeutic tones earlier than thevagus nerve stimulation or after the vagus nerve stimulation. The tonesare typically delivered at 30-second intervals. The intervals may bechanged as appropriate. The clinician may select 25 therapeutic tones.More or less tones may be selected, as appropriate. The session willtypically include 300 therapeutic tones paired with vagus nervestimulations. More or less tones may be delivered during a session, asappropriate. The therapy may include 20 sessions. More or less sessionsmay be given, as appropriate. The sessions may be provided daily.Sessions may be provided more or less often, as appropriate.

By controlling the phase of the tones in a stereo environment, the tonesmay be given the subjective attribute of apparent location. Thelocations of one or more tones may be varied, as appropriate. Inaccordance with an embodiment, various randomizations may be introduced.The selection of tones, from the therapeutic tones, for delivery to thepatient, may be randomized. The timing of the tone delivery may berandomized. In accordance with an embodiment, the tones have a 50%chance of being delivered at 15 seconds intervals, so that on average,the tones are delivered thirty seconds apart. By controlling the phaseof the tones in a stereo environment, the tones may be given thesubjective attribute of apparent location. This location of tones may berandomized.

A variety of systems and devices may be used to implement the tinnitustherapy. A percutaneous lead may be used to stimulate the vagus nerve.Because of the risk of infection is increased with a percutaneous lead,the duration of the therapy delivered will necessarily be shorter (lessthan six weeks) than is possible with an implanted lead.

As shown in FIG. 6, an implant system 100 may include an electrode 130,typically a cuff electrode. The electrode 130 is connected by a lead 120to an implantable pulse generator (IPG) 110. The electrode 130 providesthe electrical stimulation pulse train in close proximity to the vagusnerve. The lead 120 conveys the electrical current to stimulate thevagus nerve from the IPG 110 to the electrode 130. The IPG 110 includesinternal software to receive commands from a clinical controller 140 aswell as providing safety features. An example of a transcutaneouselectrical stimulation system that could be adapted for use in thedescribed therapy may be found in U.S. Pat. No. 7,797,042. Stimulationof the vagus nerve may be done at other sites along the vagus nerve andbranches of the vagus nerve.

The clinical controller 140 is connected to the IPG 110 by radiofrequency communication using a program interface 160. The ProgrammingInterface (PI) 160 has a cable with a universal serial bus (USB)connector that plugs into the clinical controller 140 and converts theinformation from the clinical controller 140 into a radio frequency (RF)signal that is transmitted to the IPG 110. The PI 160 converts thedigital signals from the computer and software into RF signals that canbe transmitted through the air and skin to the device and receives RFsignals back from the IPG 110. The IPG 110 then translates the signaland acts on the commands given it from the clinical controller 140. ThePI 160 may have a cable of at least 6 feet long and may communicate withthe IPG 110 at up to 2 meters from the PI 160. The PI 160 is powered viathe USB connection and does not require any additional power source,such as battery, or additional power connection. Other communicationmethods could be implemented as appropriate.

As shown in FIG. 7, the external controller 140, or clinical controller,is typically a laptop computer running appropriate software. Theclinical controller 140 is communicably connected to headphones 150 thatare worn by the patient. Similar automated systems are described in U.S.Pat. Nos. 6,155,971 and 7,024,398, which are incorporated herein byreference.

FIG. 8 depicts a flow chart of the patient initialization and therapyprocess. An audiogram is generated by an audiologist at 202. Thepatient's hearing loss and tinnitus frequencies are identified at 204.Therapeutic tones are selected at 206. The tones are shaped at 208. Thetones are encoded with locations at 210. The sound files are saved at212. The intensity of each tone is set and checked at 214. The therapyparameters are programmed at 216. Therapy begins at 218.

When the therapy is delivered, a tone selection process as shown in FIG.9 is used. A random tone is selected at 220. A random location isselected at 222. A playtime is determined at 224. The stimulationprocess is initiated at 226 so that the tone is played and the vagusnerve is stimulated at the same tine at 228. An end-therapy decision ismade at 230. If the therapy continues, a new random tone is selected at220. Otherwise, the therapy ends at 232.

The therapy is outlined in FIG. 10. The clinician logs into the softwareat 234. A hardware check is performed at 236. A patient set up isperformed at 238. An audiogram is input at 240. Therapeutic tones areselected at 242. The intensity of the tones is set at 244. Thestimulation parameters are set at 246. The session parameters are set at248. The therapy is delivered at 250. The therapy data is saved at 252.

A patient home therapy process is outlined in FIG. 11. A patient logsinto the software at 254. A hardware check is performed at 256. Thetherapy begins at 258. The therapy data is saved at 260.

A tone preparation process is shown in FIG. 12. A therapeutic tone isselected at 254. Each tone is encoded with location files at 256. Thetone sound files are saved at 258. The tone intensity is set at 260.

Specialized software has been developed to implement the tinnitustherapy. There are two modes in this software: At Home and Physicianmodes. The only mode available unless the Physician Login has beenaccessed and the appropriate password input is the At Home mode. In thismode only the Deliver Tinnitus Therapy option is enabled. The At Homemode allows patients to initiate a therapy session—this is the onlyfunction allowed by this mode. In order to access the rest of theprogram, the Physician Login button must be selected. This allows thePhysician to type in a password which allows access to the rest of thesoftware.

To login and access all other TAPS screens, the audiologist or physicianpresses the Physician Login button (upper right menu bar, 4th buttonfrom the right—innermost button) and enters the password. This opensfull access to the software and allows all settings to be establishedand modified. At this point the program is “unlocked” and all menus inthe program are available, as shown in FIG. 13. The first option,Audiogram, is used by the physician/audiologist to enter the audiogramdata. The second option, Therapy Tones Settings, is used by thephysician/audiologist to set the tones. The third option, ProgramImplant, is used to set the stimulation settings and allows impedancechecks. The fourth option, Deliver Tinnitus Therapy, is used only duringclinical trials. It allows the physician or audiologist to set asham-control group that does not receive paired VNS, but insteadreceives tones-only or VNS-only (in sequences such that the patientreceives tones and VNS, but they are not received simultaneously). Thisallows blinding to be maintained in a parallel study design. The “LogPatient File” option allows a patient's file to be saved. The “VNS”option allows independent delivery of VNS.

In order for therapy to be delivered, the tones and stimulation must beset by the audiologist, physician, or healthcare worker. The tones mustbe set first. To set the tones, the Audiogram and the Therapy ToneSettings tabs must be completed. The Audiogram is accessed as shown inFIGS. 14-22.

FIG. 14 is the screen where Audiogram information is added andinterpolated. The information may be loaded from a file that waspreviously generated in by the specialized software or entered manually.Once the audiogram is entered, it can be saved to a file. In order tomanually enter the data, the audiologist or physician clicks in theappropriate cells of the Audiogram Parameters table and types the valuesin as needed for frequency and hearing loss of both the Left and Rightears, as shown in FIG. 15. The user must interpolate the audiogram inorder to be able to access Therapy Tone Settings and continue withtherapy set up. In order to interpolate the data into the Therapy ToneSettings, following the successful entry of all audiogram parameters,the Interpolate button must be selected, as shown in FIG. 16. Theinterpolated data populates the Therapy Tone Parameters table on theTherapy Tone Settings automatically. This data will not be saved untileither the Save to file . . . button or the Download button is selected.The Save to file . . . function prompts the user to save the file in apreferred location (an external USB drive is recommended), and theDownload function saves the data into the IPG. In order to deliverproper therapy, the Download function must be performed so that thetherapy information is loaded into the IPG's memory.

As shown in FIG. 17, after the Audiogram parameters are populated withAudiogram-based data (either manually or from a file) and subsequentlyinterpolated, the “Therapy Tone Settings” button can be selected. TheTinnitus Frequencies can now be added. This is also where the manualtesting of the tones occurs and can be adjusted. Frequencies can bede-selected in order to notch out frequencies around the Tinnitusfrequency or frequencies.

For example, as shown in FIG. 18, if a patient has tinnitus in the leftear, around a frequency of 1,100 Hz, the audiologist is recommended tonotch out tones being played in a ½ Octave around 1,100 Hz. To do this,the frequency of 1,100 is input into the drop down menu under Left andTinnitus Frequency as shown below (right middle of screen, FIG. 18). Thesoftware will then automatically select the frequencies of 910, 1121,and 1360 Hz. If necessary, the audiologist or physician can manuallymodify this by clicking on a frequency and selecting or deselecting thefrequency.

As shown in FIG. 19, if the patient also has a tinnitus frequency of3500 in the right ear, the audiologist would add “3500” in theRight—Tinnitus Frequency box, and the software will again automatically“notch out” frequencies ½ octave around 3,500 Hz. Note that the +boxnext to the tinnitus frequency can be clicked, and additional tinnitusfrequencies can be added.

As shown in FIG. 20, two tinnitus frequencies (1,100 Hz and 3,500 Hz)are shown, and any frequency within a ½ octave of those frequencies arenotched out (inactive frequency buttons are grayed), so that thetinnitus frequencies cannot be selected.

As shown in FIG. 21, the tone volume for the sound level that each toneis played at for each frequency is also available for input. The volumeplayed in the left and right ear is adjustable—in the example below, itis 170 Hz. Frequency is being adjusted to 100 dB for both the left andright ears. The Play Left or Play Right button can be selected to testthe tones and volume levels.

FIG. 22 shows an additional three frequencies being notched-out (7278,8324, and 9506 Hz), as indicated by the gray deselected buttons near thebottom of the screen.

The Program Implant menu, as shown in FIG. 23, allows the user to setthe VNS Parameters, check the lead impedance, and then test andultimately program the parameters into the IPG. For each of the settings(Magnet, Train Duration, Amplitude, Train Period, Frequency, TrainProbability, Pulse Width, Tone Time and Therapy Duration), the box nextto the setting is clicked, and all available parameters are shown in adrop down box. The appropriate value is selected for each parameter.After all of the parameters are set, the user may Test or Program thedisplayed parameters. It is recommended the user verify that the VNSsettings chosen are tolerable for the patient. Selecting the Test buttondelivers a single train of stimulation per the parameters displayed inthe Parameters menu for this purpose. This does not permanently programthe IPG, but only performs a one-time stimulation.

Once the user is satisfied that the chosen parameters are appropriateand tolerable, the Program button must be selected in order to programthe IPG with the therapy parameters displayed in the Parameters menu.The values programmed via the Program function are input into the IPGand all subsequent therapy sessions will be performed at theseparameters. The user can modify the parameters at any time by selectingnew parameters and programming them into the IPG. The user may also wantto verify the lead impedance. In the Status portion of the ProgramImplant menu the lead impedance can be checked by selecting a Checkbutton. Doing so delivers a small current pulse through the lead tocalculate the lead impedance. The user shall ensure that the leadimpedance check does not cause discomfort in the patient. After thecheck button is selected, the lead impedance value is shown. For anyvalue above 10,000 ohms, a Warning screen above reminds the patient tocontact their physician or audiologist to see if any action needs to betaken.

As shown in FIG. 24, the therapy is delivered by selecting the PLAYbutton. For home therapy, the patient may be given limited access tosome features in the specialized software. The patient can administertherapy to themselves, and all the data corresponding to the sessionwill be recorded for subsequent review by the clinician. Headphones havebeen selected to deliver consistent tone intensity across the full rangeof frequencies. Clinical and pre-clinical data has been collected tosupport the effectiveness of the formatting.

The peripheral nervous system, central nervous system including thebrain and spinal cord can all be used as stimulation locations. Thechoice of stimulation location largely determines the behavioral andneurophysiologic outcome. Even though similar neural populations areactivated by input from two different locations, the manner in whichthey are activated, for example, the pattern of activity generatedwithin the neuron population will depend on the time course ofactivation, release of one or more neuromodulators, attention state,etc.

The neurophysiological consequences therefore are bound to be different.Given the large (and unknown) number of variables that can influence theactivation of a given neural population, the mechanisms are likely to becomplex and unpredictable. There is no calculus to determine whichlocations will produce which effects. Finding a location that produces agiven effect can only be done experimentally. It is not valid to suggestthat stimulation at one location makes it obvious to stimulate at adifferent location, even if the goal is to stimulate the same populationof neurons.

The same can be said for stimulation parameters. At a given stimulationlocation, stimulation according to one set of parameters will notnecessarily produce the same (or similar) effects as a stimulationaccording to another set of parameters. The frequency of stimulation,the current amplitude of stimulation, the duration of each stimulation,the waveform of stimulation, as well as other stimulation parameters canchange the results of stimulation.

Our experiments have shown that the effect generated by VNS pairing isvery short, less than 15 seconds. A first tone at a first frequency whenpaired with VNS generated an increase in the number of neurons thatrespond to the paired frequency. A second unpaired tone at a secondfrequency, played 15 seconds after the paired VNS did not show acorresponding increase in the number of neurons that respond to thesecond frequency. Nothing in the prior art indicates this kind ofprecise timing requirement.

Similarly, we have performed experiments in which multiple tones at agiven frequency were paired with VNS and given 30 seconds apart. Thiswas done in the tinnitus study (Engineer et al., 2011) in which VNS waspaired with each of the randomly interleaved tones every 30 seconds(e.g., 1.3 kHz+VNS, then wait for 30 seconds, then give 6.3 kHz+VNS,then wait for 30 seconds, and so on). The tones were selected such thatthey surrounded the tinnitus frequency and the tinnitus frequency itselfwas excluded. The idea was to shrink the representation of the tinnitusfrequency thereby restoring the map and synchronous activity back tonormal. When the same tones were presented 8 seconds apart, the effectwas less than if the tones were presented 30 seconds apart, which wassurprising.

To cite another example, we have performed a series of experiments wherea tone is repeatedly paired with a foot-shock to establish a conditionedfear response. Subsequently, when the tone was presented without afoot-shock, the rat would freeze, anticipating a foot shock. If thetone, without the foot-shock, is then presented repeatedly, the fearcaused by the tone would eventually be extinguished, undoing theconditioning. By pairing the tone (without the foot-shock) with VNS, thefear is extinguished much more quickly. However, presenting the tone byitself and then giving VNS minutes later, the fear is extinguished atthe normal rate. These results demonstrate that the precise timingbetween VNS and the event, as well as the interval separating theVNS-event pairings appear, to be important for inducing highly specificplasticity.”

Neurostimulation does not behave in a predictable fashion. Differentstimulation locations produce different results, even when bothlocations are cranial nerves. For example, synchronization in thecerebral cortex is a manifestation of epilepsy. Stimulating the vagusnerve causes desynchronization of the cortex neurons, which has beenproposed as a potential mechanism for how vagus stimulation prevents anepileptic seizure. Stimulation of the trigeminal nerve, another cranialnerve, causes desynchronization as well. To determine whether theplasticity induced by VNS is specific to the vagus nerve, we pairedstimulation of the trigeminal nerve with a 19 kHz tone. However, when wepaired trigeminal stimulation with a tone, in the same way we paired VNSwith a tone, we did not observe any plasticity that was specific to thepaired tone. Pairing the trigeminal stimulation with a tone at a givenfrequency did not change the response to that frequency even though itcaused desynchronization as in the previous study. Each stimulationlocation is unique across the full range of effects. It appears that VNSmay be uniquely suited to direct cortical plasticity and suggests thatthe vagus nerve is likely a key conduit by which the autonomic nervoussystem informs the central nervous system of important stimuli.

The VNS pairing therapy is more than the sum of its constituent parts.Simply playing a tone at a given frequency, without VNS, does not resultin a change in response to the frequency. Similarly, VNS by itself didnot produce any changes in response to any frequency. Only by preciselypairing VNS with a tone at a given frequency induces a change inresponse to the frequency.

Both VNS pairing and nucleus basalis stimulation (NBS) pairing have beenshown to change the number of neurons responding to a paired frequency.To be effective, the current amplitude parameter of the stimulation forVNS pairing is more than twice the current amplitude used for NBSpairing. There is an important difference between the neuromodulatorsreleased by NBS from those released by VNS, so significant differencesbetween the results of NBS and VNS are expected.

Another experiment demonstrated that pairing a single tone at aspecified frequency with VNS increased the number of neurons respondingnot only to that frequency but to close frequencies, e.g., increased thebandwidth compared to control rats. For NBS pairing, the bandwidth wasnot significantly different from control rats. Unlike VNS pairing, NBSpairing is highly invasive and may be unsuitable to provide a practicaltherapeutic benefit. Similar results in one circumstance cannot beextended to predict similar results in another, even slightly different,circumstance. Different stimulation parameters have to be used foreffective VNS pairing and NBS pairing.

We observed that 30 seconds of VNS at 30 Hz and 0.8 milliamps (mA)transiently decreased the blood oxygen saturation level (SpO₂) in 3rats. The standard 0.5 second VNS used in this study had no measurableeffect on either heart rate or oxygen saturation (data not shown). Theseresults are consistent with visual observations that brief VNS causes nonoticeable behavioral response. For example, rats did not stop groomingor awaken when brief VNS was delivered.

Our observations that brief VNS (1) caused no behavioral response, (2)caused no change in heart rate, and (3) caused no change in blood oxygensaturation, suggest that VNS induced plasticity is not equivalent topairing tones with a painful or irritating stimulus (as in footshock orair puff).

Three weeks after the end of therapy, neural recordings were obtainedfrom 13 of the 18 noise exposed rats. We continued to follow 4 rats (2therapy and 2 sham rats) for an additional two months. Consistent withprevious reports, the untreated rats continued to exhibit impaired gapdetection 3.5 months after the noise exposure. Signs of impairment ofgap detection did not return in either of the rats that received theVNS-multiple tone therapy. These results confirm that the VNS-multipletone therapy causes a long lasting reversal of noise induced perceptualhearing abnormalities in rats.

In an effort to document changes in cortical synchronization inunanesthetized rats, we looked for systematic effects of VNS-multipletone pairing on Electroencephalography (EEG) in noise exposed rats (7VNS paired and 4 VNS alone rats). Although the data is variable becausethe animal's behavioral state was uncontrolled and the EEG electrode waslocated at the vertex and not over auditory cortex, we neverthelessobserved statistically more gamma power relative to alpha in treatedrats compared to untreated rats during the last week of therapy(p<0.05), but no difference between the EEG of therapy and VNS alonerats during the first week. These results are consistent with animalstudies that tinnitus can be associated with abnormal corticalsynchronization and clinical reports of reduced alpha and increasedgamma in tinnitus patients. As in our anesthetized recordings, thedegree of EEG change was not significantly correlated with gapimpairment in individual rats.

The pairing as it relates to tinnitus is notably unique. We are notpairing just random sounds. We are not doing some kind of auditorytraining or improving perception of one sound over another. The key isthat we are deliberately pairing the non-tinnitus frequency. The reasonis that pairing the non-tinnitus frequency results in a decrease in thearea of the brain responding to the tinnitus frequency and decrease thesynchronous firing of neurons. By reducing the response to the tinnitusfrequency and decreasing synchrony, we are able to reduce tinnitussymptoms. No one has before shown that the symptoms of tinnitus can beimproved by excluding specific sounds and including specific sounds. Adrug cannot work selectively in this way, nor can cortical stimulation.VNS has the specificity to do this.

None of the description in the present application should be read asimplying that any particular element, step, or function is an essentialelement that must be included in the claim scope: the scope of patentedsubject matter is defined only by the allowed claims. Moreover, none ofthese claims is intended to invoke paragraph six of 35 USC section 112unless the exact words “means for” are followed by a participle. Theclaims as filed are intended to be as comprehensive as possible, and nosubject matter is intentionally relinquished, dedicated, or abandoned.

At least one embodiment is disclosed and variations, combinations,and/or modifications of the embodiment(s) and/or features of theembodiment(s) made by a person having ordinary skill in the art arewithin the scope of the disclosure. Alternative embodiments that resultfrom combining, integrating, and/or omitting features of theembodiment(s) are also within the scope of the disclosure. Wherenumerical ranges or limitations are expressly stated, such expressranges or limitations should be understood to include iterative rangesor limitations of like magnitude falling within the expressly statedranges or limitations (e.g., from about 1 to about 10 includes, 2, 5, 4,etc.; greater than 0.10 includes 0.11, 0.12, 0.15, etc.). For example,whenever a numerical range with a lower limit, R₁, and an upper limit,R_(u), is disclosed, any number falling within the range is specificallydisclosed. In particular, the following numbers within the range arespecifically disclosed: R=R₁+k*(R_(u)−R₁), wherein k is a variableranging from 1 percent to 100 percent with a 1 percent increment, i.e.,k is 1 percent, 2 percent, 5 percent, 4 percent, 5 percent, . . . , 50percent, 51 percent, 52 percent, . . . , 75 percent, 76 percent, 77percent, 78 percent, 77 percent, or 100 percent. Moreover, any numericalrange defined by two R numbers as defined in the above is alsospecifically disclosed. The use of the term “about” means±10 percent ofthe subsequent number unless otherwise defined. Use of the term“optionally” with respect to any element of a claim means that theelement is required, or alternatively, the element is not required, bothalternatives being within the scope of the claim. Use of broader termssuch as comprises, includes, and having should be understood to providesupport for narrower terms such as consisting of, consisting essentiallyof, and comprised substantially of. Accordingly, the scope of protectionis not limited by the description set out above but is defined by theclaims that follow, that scope including all equivalents of the subjectmatter of the claims. Each and every claim is incorporated as furtherdisclosure into the specification and the claims are embodiment(s) ofthe present disclosure. The discussion of a reference in the disclosureis not an admission that it is prior art, especially any reference thathas a publication date after the priority date of this application. Thedisclosure of all patents, patent applications, and publications citedin the disclosure are hereby incorporated by reference, to the extentthat they provide exemplary, procedural, or other details supplementaryto the disclosure.

While several embodiments have been provided in the present disclosure,it should be understood that the disclosed systems and methods might beembodied in many other specific forms without departing from the spiritor scope of the present disclosure. The present examples are to beconsidered as illustrative and not restrictive, and the intention is notto be limited to the details given herein. For example, the variouselements or components may be combined or integrated in another systemor certain features may be omitted, or not implemented.

In addition, techniques, systems, subsystems, and methods described andillustrated in the various embodiments as discrete or separate may becombined or integrated with other systems, modules, techniques, ormethods without departing from the scope of the present disclosure.Other items shown or discussed as coupled or directly coupled orcommunicating with each other may be indirectly coupled or communicatingthrough some interface, device, or intermediate component whetherelectrically, mechanically, or otherwise. Other examples of changes,substitutions, and alterations are ascertainable by one skilled in theart and could be made without departing from the spirit and scopedisclosed herein.

What is claimed is:
 1. A method of treating tinnitus comprising: determining the patient's tinnitus frequency; selecting a plurality of therapeutic tones, where the therapeutic tones are selected to be at least a half-octave above or below of the patient's tinnitus frequency; setting an appropriate volume for each of the plurality of selected therapeutic tones; repetitively playing each of the selected plurality of therapeutic tones; and pairing an electrical vagus nerve stimulation pulse train with each playing, thereby reducing the patient's perception of tinnitus.
 2. The method of claim 1, wherein respective trains are paired with respective tones of the plurality of therapeutic tones, thereby reducing the patient's perception of tinnitus.
 3. The method of claim 1, wherein respective tones of the plurality of therapeutictones are respectively at one discrete tone.
 4. The method of claim 1, wherein at least some respective tones of the plurality of therapeutic tones are respectively at two or more different tones.
 5. The method of claim 1, wherein at least some respective tones of the plurality of therapeutic tones are at different tones.
 6. The method of claim 1, wherein at least some respective tones of the plurality of therapeutic tones are respectively single frequency tones.
 7. The method of claim 1, wherein the method is implemented using a tone generator that respectively operates as a tone generator when generating at least some respective tones of the plurality of therapeutic tones.
 8. The method of claim 1, wherein at least some tones of the plurality of therapeutic tones are at one discrete tone.
 9. The method of claim 1, wherein at least some tones of the plurality of therapeutic tones are at the same frequency.
 10. The method of claim 1, further comprising: selecting at least one tone corresponding to non-tinnitus frequency tones, wherein the selected at least one tone corresponds to at least one of the plurality of therapeutic tones exposed to the patient.
 11. The method of claim 1, wherein the action of playing each of the plurality of therapeutic tones includes: exposing the patient to a respective tone at a volume different from that of another respective tone.
 12. The method of claim 1, wherein: the tones of the plurality of therapeutic tones are played at the same volume.
 13. The method of claim 1, wherein the tones of the plurality of therapeutic tones are played at one or more volumes effective to reduce the patient's perception of tinnitus.
 14. The method of claim 1, further comprising: selecting a plurality of therapeutic tones based on the determined tinnitus frequency.
 15. The method of claim 1, further comprising: determining the patient's hearing loss and the patient's tinnitus frequency.
 16. The method of claim 1, further comprising: setting respective volumes for respective tones of the plurality of therapeutic tones exposed to the patient, wherein the respective tones exposed to the patient are exposed at the respective set volumes.
 17. The method of claim 1, further comprising: at least one of determining a patient's hearing loss or measuring a patient's hearing. 